MAX Mutations Cause Hereditary and Sporadic Pheochromocytoma and Paraganglioma

NELLY BURNICHON; ALBERTO CASCÓN, ; FRANCESCA SCHIAVI,; NICOLE PAES MORALES; IÑAKI COMINO-MÉNDEZ,; NASSÉRA ABERMI; ,LUCÍA INGLADA-PÉREZ,; AGUIRRE A. DE CUBAS,; LAURENCE AMAR; MARTA BARONTINI,; SANDRA BERNALDO DE QUIRÓS,; JÉRÔME BERTHERAT; YVES-JEAN BIGNON, ; MARINUS J. BLOK,; SARA BOBISSE; SALUD BORREGO,; MAURIZIO CASTELLANO; ,PHILIPPE CHANSO; MARÍA-DOLORES CHIARA, ; ELEONORA P.M. CORSSMIT; MARA GIACCHÈRIJGER, ; , RONALD R. DE KRIJGER; TONINO ERCOLINO, ; , XAVIER GIRERD, ; ENCARNA B. GÓMEZ-GARCÍA, ; ÁLVARO GÓMEZ-GRAÑA,; ISABELLE GUILHEM, ; FREDERIK J. HES; EMILIANO HONRADO, ; ESTHER KORPERSHOEK, ; JACQUES W.M. LENDERS, ; ROCÍO LETÓN, ; ARJEN R. MENSENKAMP; , ANNA MERLO, ; LUIGI MORI, ; ARNAUD MURAT, ; PEGGY PIERRE; PIERRE-FRANÇOIS PLOUIN, ; TAMARA PRODANOV, ; MIGUEL QUESADA-CHARNECO; , NAN QIN, ; ELENA RAPIZZI, ; VICTORIA RAYMOND,; NICOLE REISCH; ,GIOVANNA RONCADOR, ; MACARENA RUIZ-FERRER, ; FRANK SCHILLO, ; ALEXANDER P.A. STEGMANN, ; CARLOS SUAREZ; ELISA TASCHIN,; HENRI J.L.M. TIMMERS, ; CARLI M.J.

CLINICAL CANCER RESEARCH

AMER ASSOC CANCER RESEARCH

Lugar: Philadelphia; Año: 2012 vol. 18 p. 2828 - 2837

1078-0432

Abstract Purpose: Pheochromocytomas (PCC) and paragangliomas (PGL) are genetically heterogeneous neural crest–derived neoplasms. Recently we identified germline mutations in a new tumor suppressor susceptibility gene, MAX (MYC-associated factor X), which predisposes carriers to PCC. How MAX mutations contribute to PCC/PGL and associated phenotypes remain unclear. This study aimed to examine the prevalence and associated phenotypic features of germline and somatic MAX mutations in PCC/PGL. Design: We sequenced MAX in 1,694 patients with PCC or PGL (without mutations in other major susceptibility genes) from 17 independent referral centers. We screened for large deletions/duplications in 1,535 patients using a multiplex PCR-based method. Somatic mutations were searched for in tumors from an additional 245 patients. The frequency and type of MAX mutation was assessed overall and by clinical characteristics. Results: Sixteen MAX pathogenic mutations were identified in 23 index patients. All had adrenal tumors, including 13 bilateral or multiple PCCs within the same gland (P < 0.001), 15.8% developed additional tumors at thoracoabdominal sites, and 37% had familial antecedents. Age at diagnosis was lower (P = 0.001) in MAX mutation carriers compared with nonmutated cases. Two patients (10.5%) developed metastatic disease. A mutation affecting MAX was found in five tumors, four of them confirmed as somatic (1.65%). MAX tumors were characterized by substantial increases in normetanephrine, associated with normal or minor increases in metanephrine. Conclusions: Germline mutations in MAX are responsible for 1.12% of PCC/PGL in patients without evidence of other known mutations and should be considered in the genetic work-up of these patients